Obtaining Stable Homogenous Mixtures with Micronized APIs

The authors examine the use of various grades of direct-compression mannitol in direct-compression tableting process to evaluate the content uniformity of micronized APIs and excipients in a solid-dosage formulation.

There are several reasons to micronize APIs in a solid-dosage formulation. Many new drug molecules are poorly soluble, and one means to enhance solubility is to enlarge surface area by micronizing the API. Obtaining a homogenous mixture of the micronized API and excipients in a solid dose and maintaining product stability, however, can be challenging. Additionally, micronized APIs are used in the formulation of highly potent drugs that require low dosage. In this case, content uniformity is crucial and difficult to achieve when seeking to evenly distribute content of less than 1% API in a solid formulation.

The pure physical mixture based on statistical distribution often has no stability of homogeneity. For this reason, many formulators switch to more expensive wet- or dry-granulation processes instead of direct compression (DC) or sachet formulations. A mixture has the best chance for stability if the particles of the API and excipients are of the same size range (1). For handling reasons, the mixture of excipients and API should be in a granulate form rather than in powdered form.

The purpose of this study was to evaluate whether such APIs could create stable mixtures with larger excipient particles and support a DC-tableting process with good content uniformity. An earlier study demonstrated the stability of so-called "ordered mixtures" with spray-dried sorbitol and much smaller API particles (2, 3). Hersey first introduced the concept of ordered mixtures to explain the behavior of interacting particles in a powder mixture (4).

These examples from the literature dealt with spray-dried sorbitol, which at the time, was a rare example of a DC excipient. Today, mannitol is used as a DC excipient due to its inertness, its low hygroscopicity and its fast-release qualities. The study in this article focuses on different DC-grades of mannitol available on the market.

Materials and methods

Table I: Physical characteristics of applied excipients and APIs*.

Two types of spray-dried DC-mannitol were used, respectively named in this study as DC-Mannitol A and DC-Mannitol M, and one type of granulated mannitol, DC-Mannitol B (see Table I). The model APIs used were ascorbic acid as an example of a hydrophilic compound and riboflavin as a hydrophobic compound. Both APIs were micronized on a pin mill before using them for this case study (see Table I).

API–mannitol mixtures (batch size 300 g) were prepared using a shaker-mixer (Turbula T2C, Willy A. Bachofen AG Maschinenfabrik). To evaluate the quality of mixing, the homogeneity was measured by taking six samples from the mixtures and applying a sample divider (Retsch Type RT 6.5, Retsch AG) after a specified period of mixing time (2, 5, 10, 20 and 30 min). The procedure was repeated three times.

Figure 1: The relative standard deviation (RSD) of the API content in relation to the mixing time of the API–direct compresson (DC)-Mannitol M samples (drug load 1% w/w). (FIGURES ARE COURTESY OF THE AUTHOR)

The API content in each sample was analyzed (n = 18). For ascorbic acid, the content was determined through a volumetric analysis by titration with an iodine solution (TitriPUR, Merck KGaA), which provided an accuracy of measurement with a relative standard deviation (RSD) of 0.12%. The riboflavin content was determined spectrophotometrically at 444 nm according to the European Pharmacopoeia (5). The RSD of the API concentration was examined as a function of mixing time (see Figures 1 and 2).

To challenge the mixture stability and to show the strength of adsorption of low-dose formulations, API–DC-mannitol mixtures with a drug content of 1% and 3% were applied to an Alpine air jet-sieve (A 200 LS, Hosokawa Alpine) and analyzed for their drug content after 15 min of airflow. The applied mesh size was 40 μm, and the vacuum pressure was 2000 mPa. Separately, the capability of a stable, direct-compression process was further investigated using a water-sensitive low-dose drug in a pharmaceutical formulation. The results of this investigation are later discussed under the "Results of field testing in a R&D case study" portion of this article.